While diagnostic imaging methods such as computerized tomography (CT) and magnetic resonance imaging (MRI) have long been employed by physicians to determine the extent of structural insults to the brain, clinical testing for the functional integrity of brain structures above the brainstem has traditionally been left to the domain of neuropsychology. Neuropsychological assessments typically involve batteries of psychometric and behavioural tests that can only be carried out on awake, alert patients who are capable of providing verbal and behavioural responses. Severe traumatic brain injury (TBI), however, commonly induces unconsciousness and/or paralysis, making standard neuropsychological testing impossible. Unfortunately, this is all too often the case for a host of brain injuries and diseases (e.g., stroke, Alzheimer's disease, Parkinson's Disease, autism, etc). The fundamental problem stems from the dependence on behavioural responses (motor or verbal), which are also invariably affected to some degree by the brain insult. This compromises the ability to conduct an assessment using behavioural responses, rendering them with definable limitations.
Case in point: For many years, the “gold standard” for testing conscious awareness has been the Glasgow Coma Scale (GCS). First reported more than 35 years ago, this long-standing clinical tool has since been followed by more sophisticated measures like the JFK Coma Recovery Scale—Revised. However, all rely on behavioural indications of consciousness. As a result, estimates of the misdiagnosis rate have been as high as 43% that is almost one out of every two people. Controversy often stems from the root of this problem, with awareness rising from cases like Terri Schiavo and Rom Houben. There remains, therefore, a disturbing lack of clinical methodology to assess the functionality of the cerebral cortex, and perhaps most importantly, the cognitive functions that subserve conscious awareness, in behaviourally unresponsive patients.
The most extreme state of behavioural unresponsiveness is coma, a condition that is thought to be caused by a dysfunction of critical brainstem structures that are responsible for producing arousal via ascending, excitatory projections to higher structures of the brain. From coma, patients may progress to a vegetative state (VS). If VS lasts more than 1-3 months, it is considered persistent. In contrast to coma, VS is characterized by intact brainstem functions, and normal sleep-wake cycles. Outward signs of purposeful or voluntary behaviour, however, are not present. Indeed, the presence of weak and inconsistent voluntary behaviour is the crucial distinguishing marker between VS, and another altered state of consciousness, the minimally conscious state (MCS). Making this distinction is a very difficult task for the clinician, who must gauge the subtle differences between reflexive movements and sporadic, weak voluntary actions. Yet another condition, locked-in syndrome (US), can mimic coma. Patients with LIS can be completely aware, yet are profoundly paralyzed, and lack voluntary control not only over their limbs, but also over the tongue, and the muscles that control the palate, jaw, and lower face. Signs of consciousness can sometimes be obtained through voluntary control over opening and closing of the eyes, but some pathologies can result in loss of this capacity, as well as the loss of pupillary reflexes. Under these circumstances, LIS can even mimic brain death.
Currently, there is no standard protocol for assessing VS versus MCS. Given the difficulty and complexity of differential diagnoses between different conditions in patients with an altered level of consciousness, it is not surprising that misdiagnoses are extremely common (close to 50%, as mentioned above). The high rate raises considerable medical, ethical, and legal concerns and places the priority on the need for better diagnosis of conscious awareness. Perhaps equally important is reduction of burden on the individual, their family, and society. While there cases in which little that can be done, once an individual has been properly evaluated as consciously aware it is possible to pursue aggressive intervention through pharmacological treatments, rehabilitation, and compensation training. None of these efforts can reasonably be justified if an individual is deemed as lacking conscious awareness.
Even more serious is the possibility for the termination of life-sustaining therapies. The decision to withhold or withdraw life-support is made by the physician, in conjunction with family members, based on their assessment of the patient's prognosis and level of consciousness. Cases such as that of Terry Schiavo have brought tremendous media attention to the clinical assessment of conscious awareness in behaviourally unresponsive patients. However, the Schiavo case gained public notice only because of the legal battle between Schiavo's mother, and her husband, who had opposite beliefs on whether Schiavo would have wished to live. The termination of life-support is in fact relatively common. In Canada, 10-20% of critically ill patients die in adult intensive care units, and 65-79% of these deaths follow the withdrawal or withholding of treatment. Given that there is increasing pressure on clinicians to terminate treatment or palliative care because of the extreme demand for ICU beds in most clinical settings, it has never been more crucial to develop methods for assessing consciousness that are not subject to the folly of depending on the capacity for behavioural response.
In recent years, there has been increasing interest in the application of functional neuroimaging methods in the assessment of consciousness. Functional neuroimaging methods such as positron emission tomography (PET) and functional MRI provide images of the neuroanatomical pattern of neural activation with good spatial accuracy. PET has been used to demonstrate that MCS patients tend to exhibit more extensive, possibly higher-level cortical processing in response to simple sounds than PVS patients. Several studies have used PET and fMRI to demonstrate residual language processing in VS, often to the subject's own name. Others claim to have demonstrated both language comprehension and volition, as demonstrated by the patient conforming to requests to imagine performing different tasks, such as walking around her house, or playing tennis. Overall, these methods provide promising means to assess conscious awareness in behaviourally unresponsive patients.
Functional MRI measurements, however, are difficult to acquire and analyze in patients with altered conscious awareness, and may not be possible with individuals who are heavily dependent on life-support. Furthermore, routinely assessing consciousness using fMRI would merely place a greater burden on an already overtaxed element of many health-care systems. In Canada, MRI wait times are currently quite long. For example, at Nova Scotia's Capital Health Care hospitals, wait times are about 80 days. In Saskatoon, Saskatchewan, the situation is far worse: a patient may wait as long as 390 days to obtain an MRI scan. Due to this critical MRI shortage, some hospitals are moving towards more strict guidelines for prioritization of MRI use. As such, it would appear unwise to establish fMRI as a primary means of assessing conscious awareness in behaviourally unresponsive patients. While wait times may improve, one thing that may not improve in the foreseeable future relates to the practical limitations of methods like MRI. MRI is large, expensive, and far from being portable. Diagnostic tests like the GCS are so pervasively used and relied on largely due to one feature—they are practical, easy to implement, and the results can be rapidly communicated. While the GCS is often administered in the ambulance and reported to medical professionals prior to or upon arrival, it is unlikely that MRI (and related technologies) will substitute for this assessment in the near future.
In contrast, electroencephalography (EEG) is an established means of examining brain function, and it has arguably the most promise for replacing existing clinical measures like the GCS. EEG is already used as a portable device in the clinic. That is, the barriers to collecting the EEG signals have largely been overcome, but more advanced uses of the technology have yet to be integrated into everyday clinical practice. For instance, measures derived from the EEG called event-related potentials (ERPs) are minute deflections normally buried in the continuous EEG that, over five decades of experimental research, have been tightly linked to discrete stages of processing in the central nervous system. Rather than measuring a correlate of neural activity derived from hemodynamic fluctuations (like fMRI), ERPs measure directly the electrical currents produced by neural activity. Furthermore, ERPs track neural activity in real time, on the order of milliseconds, therefore providing an on-line record of conscious processing (e.g., sensory, perceptual, attentional, memory, and language).
In terms of clinical applications, ERPs have been studied over the last 15 years as an objective, physiological replacement for behavioural-based neuropsychological assessment. This work resulted in a patented method for combining neuropsychological and neurophysiological approaches in aphasia assessment. The work was important foundational evidence for the general concept of decoupling the diagnosis of language function from the limitations of behavioural responses. However, it did not address critical challenges (which require novel solutions):
1) a spectrum of ERP responses exist, which can be integrated into a comprehensive test of conscious awareness. The challenge is to devise an effective method for combining this spectrum of information into a rapid and meaningful clinical test;
2) this test/method cannot be reliant on advanced expertise/training, but rather should be easy to administer, with no prior knowledge/training;
3) it should be possible to run the test on a portable, stable, noise-resistant device that is easily integrated into a wide variety of environments (small, robust, and scalable);
4) the analysis software should be provided with a database of normative subject data for comparison purposes, so as not to rely on any other standardized test or procedure; and
5) the test should produce clinically useful results (which do not require expertise to interpret), and these results should be easily output to current IT communications developments (hand held computer, wireless communications)
Early sensory evoked potentials (EPs) have long been used clinically to assess the integrity of the brainstem in coma. Longer-latency, cognitive ERPs have not yet been integrated into any routine method of clinical assessment. Research, however, has successfully employed cognitive ERPs as a neurophysiological index of mental function under a wide range of clinical conditions that preclude verbal and/or behavioural responsiveness.
For instance, Connolly and colleagues, as disclosed in U.S. Pat. No. 6,993,381 issued Jan. 31, 2006, modified existing neuropsychological tests for use in ERP recording, to perform assessments in dyslexic and aphasic patients, including one young man who suffered from global aphasia and physical disability due to a knife wound to the head. Their ERP measurements indicated that his capacity to understand language was intact, and his subsequent admission to a rehabilitation program resulted in an excellent outcome.
ERPs represent an important alternative to fMRI testing in behaviourally unresponsive patients. However, despite the fact that EEG is relatively inexpensive and can be made portable, particularly when compared to MRI technology, hospitals typically have not provided for the increased demands for EEG monitoring, both in terms of digital EEG machines, or EEG technologist coverage (Young, 2009b). There exists, therefore, considerable need for EEG technology that can be applied by non-experts, and automatically performs clinically useful tests, analyzes data without the assistance of an expert, and produces a clinically meaningful output for health care professionals. Such a device, if made portable and easy use, could not only be used widely in hospitals and clinics but also made available in a range of other settings (ambulances, arenas, nursing homes, home care etc). It could be easily integrated into the Critical Care Cascade—the continuum of care from pre-hospital assistance to ICU discharge and rehabilitation.
A wide variety of ERPs have been used in clinical research to test the functional integrity of sensory and cognitive functions in behaviourally unresponsive patients, including P1, N1, P2, MMN, P300, N400, and P600. In addition, a number of different tests have been proposed for eliciting the higher-level cognitive ERPs, including the patient's own name, nonverbal emotional exclamations, number sequences, and ERP tests based on standardized neuropsychological paper and pencil tests.
Despite the serial stages of processing that are expected to extend from early sensory ERPs to late, cognitive ERPs, it has been repeatedly demonstrated that ERP responses in patients with severely damaged central nervous systems do not necessarily conform to this hierarchy. Lower ERP responses can be lacking, while ERPs to more complex, higher processes are retained. Thus, it is important to utilize a spectrum of ERP tests/component—it is not appropriate to declare a patient cortically non-responsive as a consequence of a negative result for a single ERP.
Hierarchical paradigms also have two other important advantages: they provide a level of consistency when multiple tasks all yield negative results, and they can provide useful information about cognitive specificity when only specific responses are missing.
The following patents have been located in this general field:
U.S. Pat. No. 6,993,381B2—Linking neurophysiological and neuropsychological measures for cognitive function assessment in a patient—Connolly et al.
The above patent describes a method that utilizes audio and visual stimuli to assess language function and memory, as measured by a limited number of ERP components (N400 and P300). The complex procedure and analysis is heavily dependent on user expertise and requires an extended period for data analysis (i.e., it is intended as a neuropsychological assessment method). To that end, this method requires relating components like the N400 to computerized versions of standardized neuropsychological tests. ERP components are statistically assessed using t-tests between pairs of corresponding intervals on the waveforms to the congruent and incongruent terminal words. These intervals have a plurality of widths and are centred on the visually-identified (i.e., user-identified) peak. This method has not been designed for administration as a portable medical test which could be integrated into the Critical Care Cascade. Furthermore, its output requires expert interpretation, and has not been designed for integration with current communications developments (e.g., telecommunications) for rapid and easy communication.
U.S. Pat. No. 6,868,345B1 and WO2004/05441—Monitoring auditory evoked potentials—Jensen—commercial products by Danmeter A/S
The above patent describes a method that uses quantitative EEG measures (QEEG) from the spontaneous EEG, as well as middle-latency auditory evoked potentials (MLAEPs) and the electromyogram (EMG) to assess the depth of anaethesia. The device relies on very specific relationships between these neurophysiological indices and dosages of hypnotic agents. Drug dosage can also be added as an input to the algorithm. The device does not calculate ERR waveforms in a traditional sense.
US2007/0032737A1—Method for assessing brain function and portable automatic brain function assessment apparatus—Causevic & Combs—commercial products by BrainScope
The above patent describes a method that assesses both the spontaneous EEG using QEEG, and ERPs to potentially any type of stimuli delivered in potentially any modality. The scoring that is performed by this device is the following: classifies the brain signals as “normal” vs. “alert”, if “alert” then goes on to identify whether burst suppression or seizure activity is occurring, if none of these are occurring, it seeks to distinguish organic from non-organic (psychogenic) disorders. These indices are used to assess the neurological state of the patient by providing a single “normal” vs. “abnormal” score, and a diagnosis for an organic/psychiatric disorder. This test is not arranged to provide a standardized assessment of a spectrum of indices of information processing, including sensory and cognitive functions such as perception, attention, memory, and language comprehension. Thus it does not provide a test of conscious awareness.
U.S. Pat. No. 5,540,235—Adaptor for neurophysiological monitoring with a personal computer—Wilson
The above patent describes a method for a portable neurophysiological monitoring device that could be used to monitor ECG, EEG, or EMG. The device utilizes wireless connections.
U.S. Pat. No. 5,755,230—Wireless EEG system for effective auditory evoked response—Schmidt et al.
The above patent describes a method for a portable EEG device that communicates with a computer via a wireless connection and delivers verbal stimuli. It is specifically designed for assessing ERPs in response to verbal stimuli in small children, in order to establish whether remedial language instruction is needed. It does not perform a specific, programmed test. It simply provides a means for an experimenter to record verbal stimuli, present them, and record the ERP response.
U.S. Pat. No. 6,052,619, U.S. Pat. No. 6,385,486B1, U.S. Pat. No. 7,471,978, US2009/0076407, and US2009/0227889—Brain function scan system—John or John & John
The above documents describe a method for diagnosing brain function using QEEG, evoked potentials (EPs) from stimuli delivered in any modality, and may also utilize infrared or laser sensors to monitor cerebral blood oxygenation. The only functions assessed by EPs in this device are sensory functions, as the EPs elicited are steady-state responses analyzed by FFT. Thus, the device does not extract ERP components or assess any kind of higher-level cognitive functions.
US2009/0312663—System and method for neurometric analysis—John et al.
The above patent describes a method for establishing a server connected to a series of analysis modules which would allow remote users of their device to upload data and analyze it. The functions executed by the local or remote computer (a local computer may download these functions) include: reformatting of the data, automatically edit/remove artifacts, detect epileptiform activity, perform spectral or wavelet analysis of QEEG, transforming numerical indicators to Z-scores, perform discriminant analyses on these scores, perform source localization, and generate a report.
U.S. Pat. No. 6,223,074—Method and computer program product for assessing neurological conditions and treatments using evoked response potentials—Granger
The above patent describes a method for assessing whether or not a patient suffers from a neurological or psychiatric condition by performing a variety of ERP tests and comparing the ERP-based measures to data from healthy controls and patients suffering from that disorder. No particular test is pre-established in the program, and it appears that the user should design their own test and collect the healthy control and diagnosed patient data themselves for comparison. The patent particularly covers the extraction of the modified ERP measures, called “vectors” and “projections”, and performing a weighted vote based on correlations of those “projections” with ones from healthy subjects and disordered patients. ERP waveforms are not calculated or quantified in the traditional sense.
U.S. Pat. No. 6,317,627 (see also US2002/0082513A1 from Group 2)—Anesthesia monitoring system based on electroencephalographic signals—Ennen et al.—commercial products by Physiometrix
The above patent describes a method for a device that uses four “observers” are used to describe patient's state: Beta5 (an EMG index), Patient State Index (PSI) the main index of level of consciousness, Eyeblink, and Suppression (referring to whether burst suppression has recently been observed). This device analyzes spontaneous EEG activity: it does not present stimuli, nor use ERPs. Patient state is determined based on comparison of the QEEG measures with population norms, as well as using data from other states in the same patient. Thus, in terms of EEG measures, the device can only provide a general index of CNS depression. It does not measure any specific neural functions.
U.S. Pat. No. 6,339,721—Brain wave data processing device and storage medium—Yamazaki & Kenmochi
The above patent describes a method for using wavelet transformation to extract ERP information from single trial and averaged waveforms. On the averaged waveform, they do use a latency window for finding the ERP component, but then they search within this window using wavelet-based pattern recognition. There is also description of a basic EEG acquisition system. There is no specific test, or specific ERPs measured, it is merely an acquisition system and an automated method for ERP identification.
U.S. Pat. No. 6,493,576—Method and apparatus for measuring stimulus-evoked potentials of the brain—Dankwart-Eder
The above patent describes a method to obtain MLAEPs and brainstem auditory evoked potentials (BAEPs), for monitoring anaesthetic depth. The BAEPs are considered a “base” information signal, while the MLAEPs (or potentially other auditory ERPs) are the “variable” signal to track neurophysiological changes. This patent very specifically refers to device use only for anaesthetic monitoring. There is no automated evaluation of the ERPs, just averaging and display.
U.S. Pat. No. 6,832,110—Method for analysis of ongoing and evoked neuro-electrical activity—Sohmer et al.
The above patent describes a method for automatically evaluating ERPs in single trial data. The method can be applied to any ERP.
U.S. Pat. No. 7,373,198—Method and apparatus for the estimation of anesthetic depth using wavelet analysis of the electroencephalogram—Bibian et al.
The above patent describes a method for real-time monitoring of anesthetic depth. Anaesthetic depth is monitored by wavelet transformation of the spontaneous EEG. The description provides for possibilities of using this device to ascertain other states of the brain and well-being of the CNS (a broad-ranging list on p. 12). However, their specific claims state that they are measuring only the “level of depression in the CNS”. The method extracts wavelet coefficients from one data set and compares them to either another state in the same individual, or reference data from a group or control. No normative database is provided, the user should obtain “reference data” themselves. Thus, the device does not provide any measure of specific neural functions.
US2003/0199781 Automatic electroencephalogram analysis apparatus and method—Tsuboshita et al.
The above patent describes a method for automatically evaluating the normality/abnormality of the spontaneous EEG using QEEG measures and statistical tests in the form of Mahalanobis distance. The patient's QEEG measures are compared to a reference data set, and Mahalanobis distance is calculated from this reference data set.
US2004/0193068—Methods and apparatus for monitoring consciousness—Burton & Zilberg
The above patent describes a method for recording EEG and other physiological measures (ECG, EOG, etc.) using a novel sensor design for the purpose of depth of consciousness assessment. The device may use sleep stage analysis, EEG bispectral analysis, and auditory ERPs. They claim specifically to automatically detect whether the subject is in a transition from a conscious state to a less conscious state, or vice versa. The only auditory ERPs that are mentioned are sensory responses to click stimuli. The resulting BAEPs and MLAEPs are used as a secondary measure to compensate for the very drug agent-specific nature of bispectral (BIS) changes. It tests no specific functions of the brain beyond sensory receptivity, sleep states, and overall CNS depression.
US2008/0167570—Neural event process—Lithgow The above patent describes a method for analyzing either electrocochleogram (ECOG) data or BAEP data using wavelet transformations.
US2008/0255469 and US2009/0177108—Method for monitoring the depth of anesthesia—Shieh et al.
The above patent describes a method for monitoring depth of anaesthesia based on the spontaneous EEG. Recordings are first made on the patient in an alert, awake state. Depth of anaesthesia is then determined by entropy (a type of deviation from the original normal measurement).
US2008/0262371—Method for adaptive complex wavelet based filtering of EEG signals—Causevic
The above patent describes a method of filtering and extracting auditory ERPs using complex wavelet transformations which is explicitly applied to BAEPs but may also be used on other ERPs.
U.S. Pat. No. 5,010,891—Cerebral biopotential analysis system and method—Chamoun—commercial products by Aspect Medical Systems
The above patent describes a method that claims to assess: depth of anaesthesia, acute cerebral ischemia, level of consciousness, degree of intoxication, and ongoing normal and abnormal cognitive processes. The EEG measures used by this device are QEEG measures extracted from the spontaneous EEG. No stimuli are delivered. Specifically, its indices are third-order autocorrelations or autobispectrum (BIS) performed on either frequency-domain, or parametric values either extracted from single leads, or paired interhemispheric leads. They studied normal individuals, and patients suffering from a range of conditions, and computed what QEEG metrics served best as classifiers for those populations. These metrics are then applied in their device.
Reference is also made to the following papers, the disclosures of which are incorporated herein by reference and to which reference may be made for information to supplement the disclosure hereinafter:
Connolly, J F, D'Arcy, RCN, Newman, R L, Kemps, R. (2000). The application of cognitive event-related brain potentials (ERPs) in language-impaired individuals: Review and case studies. International Journal of Psychophysiology 38: 55-70.
D'Arcy, R C N, Connolly, J F, Service, E, Hawko, C S, Houlihan, M E. (2004). Separating phonological and semantic processing in auditory sentence processing: A high-resolution event-related potential study. Human Brain Mapping 22: 40-51.
Gawryluk, J R, D'Arcy, R C, Connolly, J F, Weaver, D F. (2010). Improving the clinical assessment of consciousness with advances in electrophysiological and neuroimaging techniques. BMC Neurology 10:11.
Kotchoubey, B, Lang, S, Mezger, G, Schmalohr, D, Schneck, M, Semmler, A, et al. (2005). Information processing in severe disorders of consciousness: Vegetative state and minimally conscious state. Clinical Neurophysiology 116: 2441-2453.
Neumann, N, Kotchoubey, B. (2004). Assessment of cognitive functions in severely paralysed and severely brain-damaged patients: Neuropsychological and electrophysiological methods. Brain Research. Brain Research Protocols 14: 25-36.
Ponton, C W, Don, M, Eggermont, J J, Kwong, B. (1997). Integrated mismatch negativity (MMNi): A noise-free representation of evoked responses allowing single-point distribution-free statistical tests. Electroencephalography and Clinical Neurophysiology: 143-150.
Rodriguez-Formells, A, Schmitt, B M, Kutas, M, Münte, T F. (2002). Electrophysiological estimates of the time course of semantic and phonological encoding during listening and naming. Neuropsychologia 40: 778-787; and
Sculthorpe, L D, Campbell, K B. (2011). Evidence that the mismatch negativity to pattern violations does not vary with deviant probability. Clinical Neurophysiology, DOI: 10.1016/j.clinph.2011.04.018
Sinkkonen, J, Tervaniemi, M. (2000). Towards optimal recording and analysis of the mismatch negativity. Audiology & Neuro-otology 5: 235-246.
Vanhaudenhuyse, A, Laureys, S, Perrin, F. (2008). Cognitive event-related potentials in comatose and post-comatose states. Neurocritical Care 8: 262-270.